Proinflammatory cytokines, especially TNF-α and interleukins (IL-β, IL-6, IL-8) play an important role in the inflammatory process. They are produced by a variety of cell types, but most important sources are macrophages and monocytes at inflammatory sites. An increase in TNF-α synthesis/release is a common phenomenon during the inflammatory process. Inflammation is an inherent part of various disease states like rheumatoid arthritis, Crohn's disease, ulcerative colitis, septic shock syndrome, atherosclerosis, among other clinical conditions.
TNF-α has been implicated as a mediator in inflammatory bowel disease, inflammation, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, osteoarthritis, refractory rheumatoid arthritis, chronic non-rheumatoid arthritis, osteoporosis/bone resorption, septic shock, endotoxic shock, atherosclerosis, ischemia-reperfusion injury, coronary heart disease, vasculitis, amyloidosis, multiple sclerosis, sepsis, chronic recurrent uveitis, hepatitis C virus infection, malaria, ulcerative colitis, cachexia, plasmocytoma, endometriosis, Behcet's disease, Wegenrer's granulomatosis, autoimmune diseases such as Crohn's disease, psoriasis or ankylosing spondylitis, immune deficiency, common variable immunodeficiency (CVID), chronic graft-versus-host disease, trauma and transplant rejection, adult respiratory distress syndrome, pulmonary fibrosis, recurrent ovarian cancer, lymphoproliferative disease, refractory multiple myeloma, myeloproliferative disorder, diabetes, juvenile diabetes, meningitis, skin delayed type hypersensitivity disorders, Alzheimer's disease, systemic lupus erythematosus and allergic asthma.
Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates immunological reactions involved in host defence, inflammation, haematopoiesis, and oncogenesis (Blood, 1989, 74(1), 1-10). IL-6 has a wide range of biological activities. It is known to be a B-cell differentiation factor, induces T cell growth and cytotoxic T-cell differentiation through effecting IL-2 receptor expression and IL-2 production. This cytokine also acts synergistically with other proteins to affect haematopoiesis, macrophage and osteoclast differentiation and platelet production. IL-6 is an interleukin that acts as both, a pro-inflammatory and an anti-inflammatory cytokine. In acute inflammation it acts as anti-inflammatory while in chronic inflammatory conditions such as collagen-induced arthritis or murine colitis, IL-6 is pro-inflammatory (Arthritis Research and Therapy, 2006, 8 (Suppl 2):S3).
IL-6 has been implicated as a mediator in inflammatory disorders, multiple myelomas, plasmacytomas, Castleman's disease, polyclonal B-cell activation and autoimmune diseases. It is secreted by T cells and macrophages to stimulate immune response to trauma, especially burns or other tissue damage leading to inflammation. It is significantly elevated with exercise, and precedes the appearance of other cytokines in the circulation. Inhibitors of IL-6 arc used to treat postmenopausal osteoporosis. IL-6 is also relevant to many diseases such as diabetes, atherosclerosis, depression, systemic lupus erythematosus, prostate cancer, and rheumatoid arthritis. Advanced/metastatic cancer patients have higher levels of IL-6 in their blood.
The first line of treatment for inflammatory disorders involves the use of non-steroidal anti-inflammatory drugs (NSAIDs) e.g. ibuprofen, naproxen to alleviate symptoms such as pain. However, despite the widespread use of NSAIDs, many individuals cannot tolerate the doses necessary to treat the disorder over a prolonged period of time as NSAIDs are known to cause gastric erosions. Moreover, NSAIDs merely treat the symptoms of disorder and not the cause. When patients fail to respond to NSAIDs, other drugs such as methotrexate, gold salts, D-penicillamine and corticosteroids are used. These drugs also have significant toxic effects.
Monoclonal antibody drugs such as Infliximab, Etanercept and Adalimumab are useful as anti-inflammatory agents, but have drawbacks such as route of administration (only parenteral), high cost and activation of latent tuberculosis. (Rheumatology, 2007, 46(5): 887-888, Clin. Infect. Dis., 39: 295-299 and Ann. Rheum. Dis., 64 (Suppl III): 86).
Despite the available treatment options for the treatment of inflammatory disorders, there still exists a need for improved and alternative medicaments for the treatment of inflammatory disorders.